News Release

Scripps Research Scientists Provide New Understanding of Chronic Pain

Findings
suggest new target for drug development

LA JOLLA, CA – January 22, 2012 –
Millions of people worldwide suffer from a type of chronic pain called
neuropathic pain, which is triggered by nerve damage. Precisely how this pain
persists has been a mystery, and current treatments are largely ineffective.
But a team led by scientists from The Scripps Research Institute, using a new
approach known as metabolomics, has now discovered a major clue:
dimethylsphingosine (DMS), a small-molecule byproduct of cellular membranes in
the nervous system. In their new study, the scientists found that DMS is
produced at abnormally high levels in the spinal cords of rats with neuropathic
pain and appears to cause pain when injected. The findings suggest inhibiting
this molecule may be a fruitful target for drug development.

"We think that this is a big step
forward in understanding and treating neuropathic pain, and also a solid
demonstration of the power of metabolomics," said Gary J. Patti, a research
associate at Scripps Research during the study, and now an assistant professor
of genetics, chemistry, and medicine at Washington University in St. Louis.
Patti is a lead author of the report on the study, which appeared online in the
journal Nature Chemical Biology on January 22, 2012.

Scientists who want to understand
what makes diseased cells different from healthy cells have often looked for
differences in levels of gene expression or cellular proteins—approaches known
respectively as genomics and proteomics. Metabolomics, by contrast, concerns
differences in the levels of small-molecule metabolites, such as sugars,
vitamins, and amino acids, that serve as the building blocks of basic cellular
processes. "These are the molecules that are actually being transformed during
cellular activity, and tracking them provides more direct information on what's
happening at a biochemical level," Patti said.

Metabolomics is increasingly used
to find biochemical markers or signatures of diseases. One of the most
relied-upon "metabolome" databases, METLIN, was set up at Scripps Research in
2005, and now contains data on thousands of metabolites found in humans and
other organisms. However, in this case the research team hoped to do more than
find a metabolic marker of neuropathic pain.

"The idea was to apply metabolomic
analysis to understand the biochemical basis of the neuropathic pain condition
and reveal potential therapeutic targets," said Gary Siuzdak, a senior
investigator in the study, who is professor of chemistry and molecular biology
and director of the Scripps Research Center for Metabolomics. "We call this
approach 'therapeutic metabolomics'."

The scientists began with a
standard model of neuropathic pain in lab rats. Patti, Siuzdak, and their
colleagues sampled segments of a previously injured tibial leg nerve triggering
neuropathic pain, as well as the rats' blood plasma and tissue from the rats'
spinal cords. The scientists then determined the levels of metabolites in these
tissues, and compared them to levels from control animals.

Unexpectedly, the scientists found
that nearly all the major abnormalities in metabolite levels were present not
in the injured leg nerve fiber, nor in blood plasma, but in tissue from the
"dorsal horn" region of the spinal cord which normally receives signals from
the tibial nerve and relays them to the brain. "After the nerve is damaged, it
degrades and rebuilds itself at the site of the injury, but remodeling also occurs,
possibly over a longer period, at the terminus of the nerve where it connects
to dorsal horn neurons," Patti said.

Next, the researchers set up a test
to see which of the abnormally altered metabolites in dorsal horn tissue could
evoke signs of pain signaling in cultures of rat spinal cord tissue. One
metabolite stood out—a small molecule that didn't appear in any of the
metabolome databases. Patti eventually determined that the molecule was DMS, an
apparent byproduct of cellular reactions involving sphingomyelin, a major
building block for the insulating sheaths of nerve fibers. "This is the first
characterization and quantitation of DMS as a naturally occurring compound,"
Patti noted. When the scientists injected it into healthy rats, at a dose similar
to that found in the nerve-injured rats, it induced pain.

DMS seems to cause pain at least in
part by stimulating the release of pro-inflammatory molecules from
neuron-supporting cells called astrocytes. Patti, Siuzdak, and their colleagues
are now trying to find out more about DMS's pain-inducing mechanisms—and are
testing inhibitors of DMS production that may prove to be effective treatments
or preventives of neuropathic pain.

"We're very excited about this
therapeutic metabolomics approach," said Siuzdak. "In fact, we're already
involved in several other projects in which metabolites are giving us a direct
indication of disease biochemistry and potential treatments."

Oscar Yanes, a postdoctoral fellow
in the Siuzdak laboratory, was Patti's co-lead author of the study,
"Metabolomics Implicates Dysregulated Sphingomyelin Metabolism in the Central
Nervous System During Neuropathic Pain." The other contributors were Leah
Shriver and Marianne Manchester of the University of California, San Diego (or
UC San Diego) Skaggs School of Pharmacy and Pharmaceutical Sciences;
Jean-Phillipe Courade, then at Pfizer, now at UCB Pharma in Belgium; and Ralf
Tautenhahn of the Siuzdak laboratory.

Funding for the research was
provided in part by the U.S. National Institutes of Health and the California
Institute of Regenerative Medicine.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.